Activation of SIRT1 by Resveratrol Alleviates Pressure Overload-Induced Cardiac Hypertrophy via Suppression of TGF-β1 Signaling

Abstract

<b><i>Introduction:</i></b> Silent information regulator 1 (SIRT1) has been extensively investigated in the cardiovascular system and has been shown to play a pivotal role in mediating cell death/survival, energy production, and oxidative stress. However, the functional role of SIRT1 in pressure overload-induced cardiac hypertrophy and dysfunction remains unclear. Resveratrol (Rsv), a widely used activator of SIRT1, has been reported to protect against cardiovascular disease. We here examine whether activation of SIRT1 by Rsv attenuate pressure overload-induced cardiac hypertrophy and to identify the underlying molecular mechanisms. <b><i>Methods:</i></b> In vivo, rat model of pressure overload-induced myocardial hypertrophy was established by abdominal aorta constriction (AAC) procedure. In vitro, Angiotensin II (Ang II) was applied to induce hypertrophy in cultured neonatal rat cardiomyocytes (NCMs). Hemodynamics and histological analyses of the heart were evaluated. The expression of SIRT1, transforming growth factor-β1 (TGF-β1)/phosphorylated (p)-small mother against decapentaplegic (Smad)3 and hypertrophic markers were determined by immunofluorescence, real-time PCR, and Western blotting techniques. <b><i>Results:</i></b> In the current study, Rsv treatment improved left ventricular function and reduced left ventricular hypertrophy and cardiac fibrosis significantly in the pressure overload rats. The expression of SIRT1 was significantly reduced, while the expression of TGF-β1/p-Smad3 was significantly enhanced in AAC afflicted rat heart. Strikingly, treatment with Rsv restored the expressions of SIRT1 and TGF-β1/p-Smad3 under AAC influence. However, SIRT1 inhibitor Sirtinol (Snl) markedly prevented the effects of Rsv, which suggest that SIRT1 signaling pathway was involved in the cardiac protective effect of Rsv. In vitro studies performed in Ang II-induced hypertrophy in NCMs confirmed the cardiac protective effect of Rsv. Furthermore, the study presented that SIRT1 negatively correlated with the cardiac hypertrophy, cardiac fibrosis, and the TGF-β1/p-Smad3 expression. <b><i>Conclusions:</i></b> Taken together, these results indicated that activation of SIRT1 by Rsv attenuates cardiac hypertrophy, cardiac fibrosis, and improves cardiac function possibly via regulation of the TGF-β1/p-Smad3 signaling pathway. Our study may provide a potential therapeutic strategy for cardiac hypertrophy.

Nutraceutical activation of Sirt1: a review

“…6 7 9-12 Moreover, measures which increase Sirt1 activity have shown benefit in rodent models of ventricular hypertrophy and heart failure. [13][14][15][16][17][18][19][20] It is therefore of importance to devise clinical strategies-preferably involving safe nutraceuticals appropriate for use in primary prevention-for enhancing Sirt1 activity. A growing literature suggests that several phytochemicals, natural metabolites and approved drugs have potential in this regard.…”

Impact of polyphenols on heart failure and cardiac hypertrophy: clinical effects and molecular mechanisms

“…RES is an activator of SIRT1, which exerts cardioprotective effects by enhancing its expression. It has been indicated that RES reduces CH and cardiac fibrosis by activating SIRT1, leading to suppression of the TGF-β1/p-Smad3 signaling pathway ( 157 ). The TGF-β/Smad3 signaling pathway is an essential regulator of fibrosis in various organs, including the heart ( 158 , 159 ).…”